CXCR1/2 antagonism with CXCL8/Interleukin-8 analogue CXCL8(3-72)K11R/G31P restricts lung cancer growth by inhibiting tumor cell proliferation and suppressing angiogenesis
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Muhammad Noman Khan1,2, Bing Wang2, Jing Wei2, Yingqiu Zhang1, Qiang Li3, Xuelin Luan1, Jya-Wei Cheng4, John R. Gordon5, Fang Li2, Han Liu1
1Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
2Department of Immunology, Dalian Medical University, Dalian, China
3Jilin Medical College, Jilin, China
4Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
5The Division of Respirology, Critical Care and Sleep Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, Canada
Fang Li, e-mail: [email protected]
Han Liu, e-mail: [email protected]
Keywords: lung cancer, G31P, CXCR antagonist, ELR-CXC chemokine
Received: January 28, 2015 Accepted: May 25, 2015 Published: June 10, 2015
CXCR1 and CXCR2 together with cognate chemokines are significantly upregulated in a number of cancers, where they act as key regulators of tumor cell proliferation, metastasis, and angiogenesis. We have previously reported a mutant protein of CXCL8/Interleukin-8, CXCL8(3–72)K11R/G31P (G31P), which can act as a selective antagonist towards CXCR1/2 with therapeutic efficacy in both inflammatory diseases and malignancies. In this study, we investigated the effect of this ELR-CXC chemokine antagonist G31P on human non-small cell lung cancer cells and lung tumor progression in an orthotopic xenograft model. We report increased mRNA levels of CXCR1 and CXCR2 in human lung cancer tissues compared to normal counterparts. Expression levels of CXCR1/2 cognate ligands was determined by ELISA. CXCR1/2 receptor antagonism via G31P leads to decreased H460 and A549 cell proliferation and migration in a dose-dependent manner. G31P also enhanced apoptosis in lung cancer cells as determined by elevated levels of cleaved PARP, Caspase-8, and Bax, together with a reduced expression of the anti-apoptotic protein Bcl-2. In an in vivo orthotopic xenograft mouse model of human lung cancer, G31P treatment suppressed tumor growth, metastasis, and angiogenesis. At the molecular level, G31P treatment was correlated with decreased expression of VEGF and NFкB-p65, in addition to reduced phosphorylation of ERK1/2 and AKT. Our results suggest that G31P blockage of CXCR1 and CXCR2 can inhibit human lung cancer cell growth and metastasis, which offers potential therapeutic opportunities.
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